Menopause & HRT Amr Nadim, MD Professor of Obstetrics & Gynecology Ain Shams Faculty of Medicine [[email protected]]

Menopause & HRT

Amr Nadim, MD Professor of Obstetrics & Gynecology

Ain Shams Faculty of Medicine[[email protected]]

POSTMENOPAUSALWOMEN’S HEALTH

Amr Nadim, MD Professor of Obstetrics &Gynecology

Ain Shams Faculty of Medicine

Objectives

• Understand major health issues facing postmenopausal women

• Understand the results of RCT’s of estrogen and how they differ from observational studies

• Learn about alternative therapies for post-menopausal women.

Menopause

• Cessation of menstrual periods due to declining estrogen and progesterone production by the ovaries

• Refers to the final menstrual period – must be free of periods for one year to be called menopause

Stages of Menopause

MenopausePost-menopausePre-

menopause

Climacteric

• Natural Menopause

– Early and Premature menopause

– Premature ovarian failure

• Induced Menopause

TYPES

• Natural Menopause diagnosis is established

when menstruation stops for 12 months in the absence of an organic or a pathological cause.

– This usually occurs at the

age of 45-50 years.

– If it occurs before the age of 40 years, it is referred to as “Premature Menopause”.

• Induced MenopauseMay be:

• Surgical after bilateral oophorectomy

• Radiological after irradiation of the ovaries

• Chemotherapeutic after exposure to chemotherapy during treatment of malignant diseases

PATHO-PHYSIOLOGY a) Endocrine Changes:

The squeal of endocrine changes is as follows:

• Decrease in inhibin production by the ovary.• Decrease in oestradiol blood level.• Increase in follicle stimulating hormone (FSH) production by the

pituitary gland (> 30 lU/ml).• Increase in lutenizing hormone (LH) production.

• The menstruation may stop abruptly but more commonly after a period of oligo and/or hypomeorrhoea.

• During this climacteric period, bleeding from a proliferative endometrium (because of anovulation) may be irregular and acyclic.– In such cases, endometrial carcinoma should be excluded before

attributing it to hormonal changes.

Hormonal Pattern after Menopause

• A state of gradual Estrogen Deprivation

• FSH and LH

• Androgens

The Menopausal Syndrome

Key Public Health Issues for Postmenopausal Women– Heart disease– Osteoporosis– Cancer– Dementia

Other Key Health Issues:– Postmenopausal Symptoms –

• Menstrual irregularities, • Vaginal dryness, • Hot flashes• Diminished libido

– Urinary Issues –• Incontinence, frequency

Menopause

chronological

cultural

psychological

biological

physiological

The Golden Rule Is :•Always try to be empathetic and NEVER underestimate your patient complaints•Avoid telling her about a complaint: “It will take its time and fade away”

Symptoms of Menopause

• Irregular menses

• Hot flashes

• Vaginal dryness

• Urinary incontinence

• Loss of Libido

Hot Flashes

What are they…?

• Sudden rush of heat to upper body, followed by

sweating and chills.

• Preceded by a prodrome of palpitations and

pressure within the head.

• A vasomotor “FLUSH” affecting the upper

thorax, neck and face may be objectively

demonstrated.

• Affect 50 to 85% women at some point:– 85% for > 1 year– 25-50% for up to 5

• 15% find them troubling and interfering with their life:– Poor quality of sleep, irritability, chronic fatigue.– Public embarassement

• 20% have more than one attack /day– Seasonal variations– Tend to occur by night

• More in Slim women who smoke

Etiology• Thermoregulatory and Vasomotor Instability

– involving α-adrenergic mechanisms and endogenous opioid peptides.

– The Hypothalamic thermostat is reset at a lower set-point

• Triggered by hormonal changes:– Estrogen Withdrawal rather tan hypoestrenemia– Pulsatile LH release– DHEA, Androstenedione, ACTH, β-lipotropin and

β-endorphin.

Estrogen

Increase Intraneuronal NE release

Inhibits NE re-uptakeIncrease Hypothalamic

α2 postsynaptic receptors

Estrogen Withdrawal seems to act through reducing α2 adrenergic Activity ERT must be given for 2-4 weeks before achieving optimal effect

because Action involves central pathways

Management• Estrogen

– Effectively stops hot flashes– Hot flashes return as soon as ERT is withdrawn– Tapering Estrogen dose over several week is advisable.

• Progestins– 10 mg Provera, 150 mg DMPA– Reseting of the hypothalamic thermostat at a higher set

point.– Side-effects

• Clonidine (Catapress)– Stabilizes the thermoregulatory mechanisms– 0.1 to 0.2 mg twice daily– Rarely used because it relieves HF by only 30 % (a little different

from placebo)

• Veralipride( Agrèal®)– 100mg daily for 20 days/month– Antidopaminergic– Side effects

• Herbs– Phytoestrogens: Soy flour, Ginseng black

Cohash

• Home remedies: – Dress in light layers; small fan to cool the face;

light bedclothes and cotton blanket– Avoid alcohol and caffeine.

Vaginal Dryness• Definition: reduced vaginal secretions and

thinning of the mucous membranes lining the vagina dryness, itching, and painful intercourse

• Cause and pathophysiology:– Declining estrogen levels– Lowered vaginal acidity– The vagina becomes shorter, narrower and inelastic– The vaginal skin becomes brittle, thin and vulnerable to

infection.

• Diagnosis– Clnical examination– Low KPI

Management

• Treatment: – Topical estrogens:

• Premarin®

• Ovestin ®

– nonprescription lubricant such as Astroglide®

• Home remedies: regular sexual activity or vegetable oils

Urinary Issues• Complaints

– Incontinence:• Stress or urge incontinence• Recurrent urethritis

• Cause: declining estrogen levels thinning of urethra and bladder tissue; anatomical changes in pelvic organs such as cystocele, rectocele or uterine prolapse

• Treatment: varies by cause; estrogen therapy may improve bladder control

• Other remedies: Kegel exercises; avoid caffeine, alcohol, and high dose Vit C; bladder retraining

Sexual Issues

• Declining libido has been long considered a companion of climacteric and postmenopause.

• Is this true?

Skin Collagen• After menopause:

– 2.1% of the skin collagen are lost per year– Up to 30% are sometime lost in the first 5

years.

• Estrogen– Improves both amount and quality of Collagen– Improves skin hydrophilic capacities– Reduces wrinkles

• Other alternatives– Moisturizing preparations– Primrose oil

Body Weight Issues

• Normal Circulating estrogen levels directs fat distribution to gynecoid fat areas.

• After menopause fat is redirected to a rather android distribution (an independent risk factor for heart disease).

• ERT:– Does NOT cause weight loss or gain– Positively affect body fat distribution.

HRT …

Estrogen…Is a Miracle Drug

• Estrogen works for hot flashes and vaginal dryness

• May help with urinary incontinence

• All types and routes of administration equally effective

• Markedly improves quality of life for younger postmenopausal women

What If…

• Contraindication to HRT

• Belief that HRT interfere with nature

• Desire to be in control

• Fear of long term effects of HRT

• Fear of adverse effects.

• lack of information about HRT

Alternatives…

• Lifestyle Changes

• Dietary changes & supplements

• Complementary therapies

• Drugs

Estrogen and Heart Disease

• A healthy 60 year old female has about a 30% lifetime risk of dying of heart disease

• Observational studies show a 35 to 50% lower risk of CAD in estrogen users

• However, results of recent clinical trials conflict with these findings

Why the Differences Between Observational Studies and RCTs for CAD?

• OS may produce the wrong answer if there are unmeasured differences between hormone users and nonusers

• Women who take HRT are generally healthier and wealthier than nonusers (some studies did not adjust for SES)

• Adherence has been shown to be a strong marker for low risk of coronary events.

• Issue of 1º versus 2º prevention of CAD• Randomization helps eliminate these and other potential

biases

HERS Conclusions

• Treatment with HRT did not reduce the overall rate of CHD events in postmenopausal women

• HRT not recommended for secondary prevention

Collaborative Group on Hormonal Factors in Breast Cancer

Analyses based on 53,865 postmenopausal women, 33% of whom had ever used HRT

• RR 1.35 for > 5 yrs HRT use• RR ~ 1.0 if < 5 yrs since HRT use• Ever HRT users had tumors that were less

advanced clinically• Effect on mortality unclear

Lancet 1997

WHI Estrogen+Progestin TrialSpecific Aims

• To test whether E+P:

• Reduces the incidence of CHD and other CVD

• Reduces the incidence of all osteoporosis-related fractures and hip fractures separately

• Increases the risk of breast cancer

Profile of the Women’s Health Initiative Randomized Trial ofEstrogen Plus Progestin in Women With an Intact Uterus

Provided consent and reportedno hysterectomy (N = 18,845)

Initiated screening (N = 373,092)

Randomized (N = 16,608)

Status on 4/30/02 Alive/outcomes data

submitted in last 18 months (n = 7,968)

Unknown vital status (n = 307)

Deceased (n = 231)

Estrogen +Progestin(N = 8,506)

Status on 4/30/02 Alive/outcomes data

submitted in last 18 months (n = 7,608)

Unknown vital status (n = 276)

Deceased (n = 218)

Placebo(N = 8,102)

Attributable Risk Summary

• Excess risk per 10,000 person-years on E+P– 7 more women with CHD– 8 more women with stroke– 8 more women with PE– 8 more women with breast cancer

• Risk reduction per 10,000 person-years on E+P– 6 fewer colorectal cancer– 5 fewer hip fractures

• Summary: 19 additional monitored events per 10,000 person years on E+P

WHI Estrogen+Progestin TrialSummary

• Treatment with estrogen plus progestin for up to 5

years is not beneficial overall.

• There is early harm for CHD, continuing harm for

stroke and VTE, and increasing harm for breast

cancer.

• This risk-benefit profile is not consistent with a

viable intervention for primary prevention of

chronic diseases in postmenopausal women.

WHI Estrogen+Progestin TrialImplications

• Estrogen plus progestin should not be initiated or continued for the primary prevention of CHD.

• The risks for CHD, stroke, PE and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis.

Why Alternatives to HRT are requested?

• Contraindication to HRT

• Belief that HRT interfere with nature

• Desire to be in control

• Fear of long term effects of HRT

• Fear of adverse effects.

• Lack of information about HRT

Facts about alternatives for HRT

1.Most treat only a single problem

2.There is potential harm, because of a lack of efficacy or possible risks

3.There is a lack of evidence to confirm benefits or possible adverse effects.

4.There is a widespread belief that “natural” means harmless, but herbs may contain potent chemicals & should be used with caution.

Alternatives to HRT

• Lifestyle Changes

• Dietary changes & supplements

• Complementary therapies

• Drugs

Life Style Changes

• Avoidance of Triggers for Vasomotor Changes

• Avoidance of Risk Factors for osteoporosis

• Exercise

Multivitamins

• Vit E: 400-1200 IU daily– Reduces VM symptoms (Kass-

Annesse,2000)– Reduces the risk of CHD (100 IU daily for 2

years) – Low level of Vit E is a better predictor of CHD

than elevated cholesterol or blood pressure (Cooper et al,1994)

• Vitamin D: 400 IU daily with calcium significantly reduced fracture risk (Chapuy et al, 1992)

• Oily fish eaten at least twice a week reduced mortality from CHD (Daviglus et al, 1997)

• Garlic: reduction of cholesterol is doubtful (Daviglus et al, 1997)

Minerals

• Adequate calcium intake: 1500 mg daily: reduction of hip fracture (Cumming et al, 1997).

• Adequate intake of magnesium is crucial for osteoporosis prevention (Kass-Annesse,2000).

• The dietary ratio of calcium to magnesium is best maintained at 2:1.

•

Selective Estrogen Receptor Modulators (SERM)

SERMs are compounds that engage the estrogen receptors and– exert estrogen agonist effects in desired target tissues such as

bone and the cardiovascular system – together with estrogen antagonism (or clinically neutral effect) in

the reproductive tissues such as the uterus and breast. this is differential activity in human tissues.

– Tamoxifen: Is a first generation SERM.– Raloxifen: Is a benzothiophene derivative and comes closer to be

the ideal estrogen. • It displayes activity against breast cancer comparable to tamoxifen,

selectivity inhibited uterine tissues, and simultaneously maintained bone density and favorable serum lipid profile,

• yet failed to control postmenopausal vasomotor symptoms and even may exagerate them..

Tibolon • Tibolon is a steroid with tissue-specific activities which has

the capacity to exert estrogenic or progestogenic/androgenic effects, depending on the tissue substrate.

• These tissue-specific properties of tibolon enable it to act in specific parts of the body like an estrogen: – Providing effective relief of climacteric symptoms. – Preventing osteoporotic bone loss. – Having beneficial androgenic effects on mood and libido.

• Tibolon has the following advantages: – On the endometrium: It does not act as an estrogen. Therefore does

not stimulate endometrial proliferation. In contrast to conventional HRT, the use of Tibolon does not require the addition of a progestogen to induce regular withdrawal bleedings to limit endometrial proliferation, nor to protect against endometrial hyperplasia.

– On the breast tissue: It does not act as an estrogen in breast tissue. This leads to low incidence of breast tenderness and causes no increased mammographic density.

Avoid factors increasing urinary calcium loss

• High sodium intake

• High phosphorus (soft drinks such as cola) & may be damaging for young bone (Carey & Carey, 1999).

• High protein intake, generally in the form of animal protein (Nordin, 2000).

• High caffeine intake is associated with an increase in fracture

Natural hormonesA. Phytoestrogens [Derived from plants ]

– Asian women experience fewer menopausal symptoms than western women & their traditional diet contain high level of phytoestrogens, about 200 mg daily compared with < 5 mg daily in western diet.

• Types– Isoflavones: soya beans (richest source), chick peas, lentils– Lignans: apples, stone fruits, onion, garlic, seed oils, cereals,

fruit & vegetables. – Coumestans: clover

• Available in: – tablet (Klimadynon=cimicifugae)– food supplements in bread, – snack bars, – health drinks.

Natural progestagen creams

• Extracted from: plant source, mainly yams & soya.

• Effects: An improvement in vasomotor symptoms but no effect on bone

Dehydroepiandrosterone (DHEA)

• Available as: a food supplement.

• Effects: – improved mood, sleep, tiredness & ability to

cope (Thaker & Booher, 1999).

• Adverse effects: – lowering HDLP, increasing insulin resistance

& raising blood pressure

Complementary Therapy

• Herbalism.

• Acupuncture.

• Stress reduction.

• Homoeopathy

Herbalism:[There is a widespread belief that “natural” means harmless, but herbs may contain

potent chemicals & should be used with caution]

• Black cohosh (Cimmicifugae racemosae)– Effective in alleviation of vasomotor symptoms,

insomnia & low mood (Mckenna et al, 2001). – Daily dose: 40 mg & no longer than 6 months. – No drug interaction.

• St John s Wort (Hypericum)– Dose: 900 ug daily. – Effective in reducing flushes, low mood, insomnia

(Grube et al, 1999). – Drug interactions include: theophylline, digoxin,

cyclosporin, combined oral contraceptive pills.

• Valerian, sage, chste tree, dong quai, ginseng, gingko biloba, kava, garlic, & feverfew: Comission E does not recommend them for use at menopause (2002) because of Limited scientific data or adverse side effects.

• Oil of evening primrose in a placebo RCT is not effective (Chenoy et al, 1994)

• Chinese herbs are not effective in placebo RCT (Davis et al, 2001)

For prevention & treatment of osteoporosis

• Bisphosphonates– Alendronates: Fosamax– Residronates: Actonelle

• Raloxifene and other SERMs– Evista

• Tibolone: Livial

For treatment of vasomotor symptoms• Antidepressants:

– For hot flushes. Also positive effect on mood & libido, – Adverse effects: dry mouth, nausea, constipation, & reduced appetite

• Paroxetine (seroxat) (20 mg daily): 67% reduction in hot flushes (Stearns et al, 2000)• Venlafaxine (Efexor) (75 mg daily): 61% reduction (Loprinzi, 2000) (RCT). The benefits

are seen within a couple of weeks. • Venlafaxine 37.5 mg daily: 37% reduction of hot flushes & fewer adverse effects

• Night sedation:– For insomnia & mood swings

• Veralipide (agreal): – 100 mg daily for 20 days, repeated after 10 days. It is neuroliptic

• Propranolol:– No data to support its use (Brockie, 2002)

• Bellergal-Retard: – phenobarbitone (central sedative 40 mg), belladona (parasympathetic inhibitor, 0.2

mg), ergometrin tartarate (sympathetic inhibitor, 0.6 mg) one tab twice daily• Clonidine (catapress):

– 0.1 to 0.2 mg twice daily– Rarely used because 30 % reduction which is little different from placebo (Laufer,

1982)• Gabapentin (Guttuso, 2000). (Uncontrolled study)

For symptomatic treatment of atrophic vaginitis

• Simple vaginal lubricants:– Astroglide, Lubrin, replens

• Long acting bioadhesive vaginal moisturiser: – It is comparable to vaginal estrogen preparation

(Nachtigal,1994). – It is a gel containing water & polycarbophil that adhere to

the vaginal wall, encouraging water back into the dehydrated cells. Each application lasts for about 3 days.

• Vaginal estriol or estradiol:– It is not absorbed systemically to any significant degree. – They can be used safely in women with a contraindication

to systemic estrogen .